Project Summary/Abstract A 3-yr fellowship project is proposed to develop a novel method to electrically stimulate the spinal cord. The applicant has a unique and strong history in spinal cord electrical stimulation, and a PhD project and training program has been designed to build upon his existing strengths while developing a new methodology. The new method is called temporal interference (T-I) stimulation, and will be used to restore respiratory muscle activation during acute or chronic hypoventilation following opioid overdose or neurotrauma. The premise is to target the spinal cord with two, high frequency, but low amplitude electrical waveforms. The waveforms are delivered at kilohertz frequencies that are well above values that directly stimulate neurons. The frequency of the two waveforms is offset by a small amount (e.g. 1-5 Hz), and where the two electrical fields sum in the tissue, neuronal populations are recruited in phase with the offset. In preliminary experiments, the applicant delivered T-I stimulation using simple sub-cutaneous neck electrodes following acute opioid overdose in adult rats. Remarkably, this approach was able to evoke diaphragm motor recruitment, and the discharge could be regulated by varying the offset frequency between the two stimulus waveforms. Additional preliminary experiments focused on epidural spinal cord stimulation. Electrodes on the mid-cervical dorsal epidural surface were used to deliver two kilohertz waveforms, and this was remarkably effective at activating and regulating diaphragm motor units. Compared to traditional single wave epidural stimulation, we predict that T-I will offer advantages including 1) improved efficacy after incomplete and/or chronic lesions; 2) ability to produce diaphragm motor unit recruitment with a more natural ?burst? envelope, and 3) ability to more focally target the stimulus to the ventral horn. The overall hypothesis guiding this proposal is that T-I stimulation can be used to target energy to the ventral cervical spinal cord to regulate diaphragm activation with minimal off target effects. This will be tested by evaluating and optimizing T-I stimulation delivered via subcutaneous (Aim 1) or epidural electrodes (Aim 2). This PhD project is highly innovative since dual waveform T-I stimulation has not previously been explored as a means of activating the respiratory muscles. Primary mentor Dr. Fuller has an NIH-funded laboratory and an excellent track record of successfully mentoring PhD students. A carefully developed training plan includes coursework in research design, statistics and ethics, participation in active journal clubs and seminar series, attendance at national conferences, and training in new research techniques. This fellowship targets development of novel strategies to restore ventilation in case of drug overdose and spinal cord injury while helping to develop the career of a highly promising young scientist.